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辉瑞潜在重磅药物Xeljanz银屑病III期研究达主要终点
2014-05-25
来源：生物谷
辉瑞（Pfizer）5月23日公布了口服Janus激酶（JAK）抑制剂tofacitinib（托法替尼，商品名：Xeljanz）III期OPT Retreatment (A3921111)研究的详细结果，该研究调查了tofacitinib用于中度至重度慢性斑块型银屑病成人患者的治疗。数据表明，tofacitinib 5mg和10mg每日2次（BID）疗法，均达到了2个主要疗效终点。该项研究中，安全性数据与此前研究一致。
OPT Retreatment (A3921111)是一项为期56周的研究，在中度至重度慢性斑块型银屑病成人患者中开展，比较了tofacitinib 5mg和10mg BID疗法撤出（withdrawal）和复治（retreatment）相对于安慰剂的疗效和安全性。研究数据表明，在停药期间（withdrawal phase），与切换至安慰剂治疗的患者组相比，继续接受tofacitinib治疗的患者组有更大比例的患者维持了治疗反应（5mg BID和10mg BID实现PASI75的患者比例为44%和68%，实现PGA的患者比例为43%和63%），5mg和10mg BID剂量均达到了首个主要疗效终点。
此外，在失去足够治疗反应（PASI75或PGA降低50%）的患者中，在接受tofacitinib复治（retreatment）后，许多患者能够重新获得治疗反应（5mg BID和10mg BID实现PASI75的患者比例为36.8%和61.0%，实现PGA的患者比例为44.8%和57.1%），5mg和10mg BID剂量均达到了第2个主要疗效终点。
OPT Retreatment研究的数据将为医生在临床实践中提供相关资料，因为在临床治疗中，患者停止和重新治疗现象很常见。
tofacitinib的III期OPT（口服治疗银屑病）项目包括5个III期研究，该项目是迄今为止在中度至重度慢性斑块型银屑病中开展的全球最大的临床试验项目。
关于tofacitinib（Xeljanz）：
tofacitinib是一种新颖的口服Janus激酶（JAK）抑制剂，目前正在调查用于中度至重度慢性斑块型银屑病成人患者的治疗。该药由辉瑞科学家发现和开发，具有一种新颖的作用机制，旨在抑制JAK通路，这些通路被认为在银屑病慢性炎症反应中发挥了重要作用。通过抑制这些JAK通路，tofacitinib能够降低细胞因子信号传导、细胞因子诱导的基因表达及细胞的激活。
tofacitinib已获全球20多个国家批准，用于中度至重度类风湿性关节炎（RA）的治疗。在美国，tofacitinib商品名为Xeljanz（5mg片剂），获批用于对甲氨蝶呤反应不足或不耐受的中度至重度活动性类风湿性关节炎成人患者的治疗。（生物谷Bioon.com）
英文原文：Pfizer Announces Detailed Results For Phase 3 OPT Retreatment Study Of Tofacitinib In Adults With Moderate-To-Severe Chronic Plaque Psoriasis
Findings Presented During 11th European Academy of Dermatology and Venereology Spring Symposium in Belgrade, Serbia
Friday, May 23, 2014 - 9:13am EDT
Pfizer Inc. (NYSE:PFE) announced today detailed results from the Oral treatment Psoriasis Trial (OPT) Retreatment study (A3921111), a Phase 3 study investigating tofacitinib for the treatment of adult patients with moderate-to-severe chronic plaque psoriasis. This three-period study showed that tofacitinib, as a 5 mg or 10 mg pill taken twice daily, met its two primary efficacy endpoints. The safety profile of tofacitinib in OPT Retreatment was consistent with previous studies and there were no new safety findings in this trial.
The first primary endpoint of OPT Retreatment evaluated the maintenance of clinical response in patients who remained on tofacitinib after an initial treatment phase compared to patients who were switched to placebo (withdrawal phase). The second primary endpoint examined patients who lost half of their original clinical response during the withdrawal phase, and measured the proportion of these patients who regained their original clinical response after restarting treatment with tofacitinib. Throughout the study, the efficacy response was measured by the proportion of subjects achieving a Physician’s Global Assessment (PGA) response of “clear” or “almost clear” skin and the proportion of subjects achieving at least a 75% reduction in the Psoriasis Area and Severity Index (PASI75), two commonly used measures of efficacy in psoriasis.
“Psoriasis is a chronic disease that affects approximately two-to-three percent of people worldwide, and there are times when patients with psoriasis may need to stop and restart therapy for medical or non-medical reasons, such as elective surgery or receipt of live immunizations,” said lead investigator Robert Bissonnette, M.D., Innovaderm Research, Montreal, QC, Canada. “The OPT Retreatment data showed that patients who stayed on therapy with tofacitinib maintained their rates of response and for those who stopped therapy, a proportion of patients were able to regain their original clinical response when retreated with tofacitinib.”
Tofacitinib, an oral Janus kinase (JAK) inhibitor, is part of a new class of medicines in development for the treatment of moderate-to-severe plaque psoriasis. Top-line results from OPT Retreatment were previously announced in October 2013, and the detailed results of this study were shown today in an oral presentation during the 11th European Academy of Dermatology and Venereology (EADV) Spring Symposium in Belgrade, Serbia.
OPT Retreatment was a Phase 3 randomized, double-blind, three-period, parallel group, placebo-controlled 56-week study. This study evaluated the efficacy and safety of the withdrawal and retreatment with tofacitinib 5 mg and 10 mg twice daily compared to placebo in 674 adult patients with moderate-to-severe chronic plaque psoriasis. During the first period (24 weeks), which was a secondary endpoint of this study, patients were treated with either tofacitinib at a dose of 5 mg or 10 mg twice daily in a blinded manner. During this initial 24 weeks of treatment:44% and 68% of patients who received tofacitinib 5 mg and 10 mg twice daily achieved at least a 75% reduction in the Psoriasis Area and Severity Index (PASI75), respectively, and42% and 63% of patients who received tofacitinib 5 mg and 10 mg twice daily achieved a PGA response of “clear” or “almost clear” skin, respectively.
The patients who achieved a PASI75 and PGA response were then randomized to either continue tofacitinib or switch to placebo for 16 weeks or until they lost half of their original PASI response to treatment, whichever occurred first. During this withdrawal period: A statistically significantly greater proportion of patients who remained on both doses of tofacitinib maintained PASI75 and PGA responses relative to patients who were switched to placebo, and
No patients experienced psoriasis rebound (rapidly spreading psoriasis after treatment withdrawal).
In the retreatment period, all patients resumed their original tofacitinib dose until week 56. After 16 weeks of restarting therapy with tofacitinib, the efficacy response was evaluated in the proportion of patients who lost half of their original PASI or PGA response during the withdrawal phase and showed that:36.8% and 61.0% of patients who received tofacitinib 5 mg and 10 mg twice daily, respectively, achieved a PASI75; and44.8% and 57.1% of patients who received tofacitinib 5 mg and 10 mg twice daily, respectively, achieved a PGA of “clear” or “almost clear” skin.
The most common adverse events for all study periods were nasopharyngitis and upper respiratory tract infection. There was one cardiac-related death that occurred during the OPT Retreatment study at the 5 mg dose. However, in the opinion of the investigator, there was not a reasonable possibility that this death was related to tofacitinib.
OPT Retreatment is one of five studies from the Phase 3 OPT Clinical Trial Program, one of the largest global clinical trial programs in moderate-to-severe chronic plaque psoriasis to date. The results from this study will be included in the planned tofacitinib psoriasis submission package to regulatory authorities in various markets. Pfizer currently intends to submit a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) for the approval of tofacitinib for the treatment of adults with moderate-to-severe chronic plaque psoriasis by early 2015.
About the OPT Clinical Trial Program
The Phase 3 OPT clinical trial program consists of five studies (including one long-term extension study) evaluating oral tofacitinib 5 mg and 10 mg twice daily in adults with moderate-to-severe chronic plaque psoriasis. It is a global, comprehensive clinical development program that includes over 3,600 patients in 36 countries, and is one of the largest global clinical trial programs in moderate-to-severe chronic plaque psoriasis to date. In addition to the OPT Retreatment study, the OPT Program includes the following Phase 3 studies of tofacitinib in adults with moderate-to-severe plaque psoriasis:
OPT Pivotal #1 (A3921078) and OPT Pivotal #2 (A3921079): OPT Pivotal #1 and OPT Pivotal #2 are 52-week, randomized, double-blind, placebo-controlled, parallel-group studies evaluating the safety and efficacy of tofacitinib 5 mg and 10 mg twice daily in patients who are candidates for systemic therapy or phototherapy. There were over 900 patients randomized into the each of the studies. As previously announced in April 2014, the OPT Pivotal #1 and OPT Pivotal #2 studies showed that tofacitinib, as a 5 mg or a 10 mg dose taken as a pill twice daily, met the primary efficacy endpoints of statistically significant superiority over placebo at Week 16 in the proportion of subjects achieving a PGA response of “clear” or “almost clear” skin, and the proportion of subjects achieving at least a 75% reduction in Psoriasis Area and Severity Index (PASI75).
OPT Compare (A3921080): A 12-week, Phase 3 study comparing the efficacy and safety of tofacitinib 5 mg and 10 mg twice daily to high-dose ENBREL® (etanercept) 50 mg twice weekly as well as to placebo. There were 1,106 patients enrolled in this study.
OPT Extend (A3921061): A long-term extension study evaluating the safety and tolerability of tofacitinib. Patients who participated in the Phase 2 trial or any of the other Phase 3 studies had the option, if eligible, to enroll in this study.
About Plaque Psoriasis
Psoriasis is a chronic, immune-mediated disease, affecting primarily the skin but also other organs, such as nails and joints. It affects approximately two-to-three percent of people worldwide and 7.4 million people in the United States.1,2,3,4,5,6,7 Due to inconsistent response to treatment, adverse effects, and the limited persistence of therapeutic effects of some therapies, a need for additional therapies for patients with moderate-to-severe chronic plaque psoriasis remains.8,9,10 According to recent published surveys, approximately 50 percent of patients with psoriasis are dissatisfied with their treatment and under-treatment represents a significant problem. Even though guidelines typically state that moderate-to-severe patients are candidates for systemic therapy – e.g., medicines given by mouth or an injection - many adult plaque psoriasis patients appear to be undertreated. Approximately 30 percent of treated moderate patients and 22 percent of treated severe patients receive only topical therapies like ointments and creams in the U.S.11
XELJANZ® (tofacitinib citrate) 5 mg Tablets RA U.S. Label Information
Tofacitinib is currently approved in more than 20 countries around the world for the treatment of moderate-to-severe rheumatoid arthritis. In the U.S., the brand name for tofacitinib is XELJANZ® (ZEL’ JANS’), and it is approved at the 5 mg dose for the treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate.
XELJANZ is a prescription medicine called a Janus kinase (JAK) inhibitor. XELJANZ is used to treat adults with moderately to severely active rheumatoid arthritis in which methotrexate did not work well.
It is not known if XELJANZ is safe and effective in people with Hepatitis B or C.
XELJANZ is not for people with severe liver problems.
It is not known if XELJANZ is safe and effective in children.
OPT Retreatment (A3921111)是一项为期56周的研究，在中度至重度慢性斑块型银屑病成人患者中开展，比较了tofacitinib 5mg和10mg BID疗法撤出（withdrawal）和复治（retreatment）相对于安慰剂的疗效和安全性。研究数据表明，在停药期间（withdrawal phase），与切换至安慰剂治疗的患者组相比，继续接受tofacitinib治疗的患者组有更大比例的患者维持了治疗反应（5mg BID和10mg BID实现PASI75的患者比例为44%和68%，实现PGA的患者比例为43%和63%），5mg和10mg BID剂量均达到了首个主要疗效终点。
此外，在失去足够治疗反应（PASI75或PGA降低50%）的患者中，在接受tofacitinib复治（retreatment）后，许多患者能够重新获得治疗反应（5mg BID和10mg BID实现PASI75的患者比例为36.8%和61.0%，实现PGA的患者比例为44.8%和57.1%），5mg和10mg BID剂量均达到了第2个主要疗效终点。
OPT Retreatment研究的数据将为医生在临床实践中提供相关资料，因为在临床治疗中，患者停止和重新治疗现象很常见。
tofacitinib的III期OPT（口服治疗银屑病）项目包括5个III期研究，该项目是迄今为止在中度至重度慢性斑块型银屑病中开展的全球最大的临床试验项目。
关于tofacitinib（Xeljanz）：
tofacitinib是一种新颖的口服Janus激酶（JAK）抑制剂，目前正在调查用于中度至重度慢性斑块型银屑病成人患者的治疗。该药由辉瑞科学家发现和开发，具有一种新颖的作用机制，旨在抑制JAK通路，这些通路被认为在银屑病慢性炎症反应中发挥了重要作用。通过抑制这些JAK通路，tofacitinib能够降低细胞因子信号传导、细胞因子诱导的基因表达及细胞的激活。
tofacitinib已获全球20多个国家批准，用于中度至重度类风湿性关节炎（RA）的治疗。在美国，tofacitinib商品名为Xeljanz（5mg片剂），获批用于对甲氨蝶呤反应不足或不耐受的中度至重度活动性类风湿性关节炎成人患者的治疗。（生物谷Bioon.com）
英文原文：Pfizer Announces Detailed Results For Phase 3 OPT Retreatment Study Of Tofacitinib In Adults With Moderate-To-Severe Chronic Plaque Psoriasis
Findings Presented During 11th European Academy of Dermatology and Venereology Spring Symposium in Belgrade, Serbia
Friday, May 23, 2014 - 9:13am EDT
Pfizer Inc. (NYSE:PFE) announced today detailed results from the Oral treatment Psoriasis Trial (OPT) Retreatment study (A3921111), a Phase 3 study investigating tofacitinib for the treatment of adult patients with moderate-to-severe chronic plaque psoriasis. This three-period study showed that tofacitinib, as a 5 mg or 10 mg pill taken twice daily, met its two primary efficacy endpoints. The safety profile of tofacitinib in OPT Retreatment was consistent with previous studies and there were no new safety findings in this trial.
The first primary endpoint of OPT Retreatment evaluated the maintenance of clinical response in patients who remained on tofacitinib after an initial treatment phase compared to patients who were switched to placebo (withdrawal phase). The second primary endpoint examined patients who lost half of their original clinical response during the withdrawal phase, and measured the proportion of these patients who regained their original clinical response after restarting treatment with tofacitinib. Throughout the study, the efficacy response was measured by the proportion of subjects achieving a Physician’s Global Assessment (PGA) response of “clear” or “almost clear” skin and the proportion of subjects achieving at least a 75% reduction in the Psoriasis Area and Severity Index (PASI75), two commonly used measures of efficacy in psoriasis.
“Psoriasis is a chronic disease that affects approximately two-to-three percent of people worldwide, and there are times when patients with psoriasis may need to stop and restart therapy for medical or non-medical reasons, such as elective surgery or receipt of live immunizations,” said lead investigator Robert Bissonnette, M.D., Innovaderm Research, Montreal, QC, Canada. “The OPT Retreatment data showed that patients who stayed on therapy with tofacitinib maintained their rates of response and for those who stopped therapy, a proportion of patients were able to regain their original clinical response when retreated with tofacitinib.”
Tofacitinib, an oral Janus kinase (JAK) inhibitor, is part of a new class of medicines in development for the treatment of moderate-to-severe plaque psoriasis. Top-line results from OPT Retreatment were previously announced in October 2013, and the detailed results of this study were shown today in an oral presentation during the 11th European Academy of Dermatology and Venereology (EADV) Spring Symposium in Belgrade, Serbia.
OPT Retreatment was a Phase 3 randomized, double-blind, three-period, parallel group, placebo-controlled 56-week study. This study evaluated the efficacy and safety of the withdrawal and retreatment with tofacitinib 5 mg and 10 mg twice daily compared to placebo in 674 adult patients with moderate-to-severe chronic plaque psoriasis. During the first period (24 weeks), which was a secondary endpoint of this study, patients were treated with either tofacitinib at a dose of 5 mg or 10 mg twice daily in a blinded manner. During this initial 24 weeks of treatment:44% and 68% of patients who received tofacitinib 5 mg and 10 mg twice daily achieved at least a 75% reduction in the Psoriasis Area and Severity Index (PASI75), respectively, and42% and 63% of patients who received tofacitinib 5 mg and 10 mg twice daily achieved a PGA response of “clear” or “almost clear” skin, respectively.
The patients who achieved a PASI75 and PGA response were then randomized to either continue tofacitinib or switch to placebo for 16 weeks or until they lost half of their original PASI response to treatment, whichever occurred first. During this withdrawal period: A statistically significantly greater proportion of patients who remained on both doses of tofacitinib maintained PASI75 and PGA responses relative to patients who were switched to placebo, and
No patients experienced psoriasis rebound (rapidly spreading psoriasis after treatment withdrawal).
In the retreatment period, all patients resumed their original tofacitinib dose until week 56. After 16 weeks of restarting therapy with tofacitinib, the efficacy response was evaluated in the proportion of patients who lost half of their original PASI or PGA response during the withdrawal phase and showed that:36.8% and 61.0% of patients who received tofacitinib 5 mg and 10 mg twice daily, respectively, achieved a PASI75; and44.8% and 57.1% of patients who received tofacitinib 5 mg and 10 mg twice daily, respectively, achieved a PGA of “clear” or “almost clear” skin.
The most common adverse events for all study periods were nasopharyngitis and upper respiratory tract infection. There was one cardiac-related death that occurred during the OPT Retreatment study at the 5 mg dose. However, in the opinion of the investigator, there was not a reasonable possibility that this death was related to tofacitinib.
OPT Retreatment is one of five studies from the Phase 3 OPT Clinical Trial Program, one of the largest global clinical trial programs in moderate-to-severe chronic plaque psoriasis to date. The results from this study will be included in the planned tofacitinib psoriasis submission package to regulatory authorities in various markets. Pfizer currently intends to submit a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) for the approval of tofacitinib for the treatment of adults with moderate-to-severe chronic plaque psoriasis by early 2015.
About the OPT Clinical Trial Program
The Phase 3 OPT clinical trial program consists of five studies (including one long-term extension study) evaluating oral tofacitinib 5 mg and 10 mg twice daily in adults with moderate-to-severe chronic plaque psoriasis. It is a global, comprehensive clinical development program that includes over 3,600 patients in 36 countries, and is one of the largest global clinical trial programs in moderate-to-severe chronic plaque psoriasis to date. In addition to the OPT Retreatment study, the OPT Program includes the following Phase 3 studies of tofacitinib in adults with moderate-to-severe plaque psoriasis:
OPT Pivotal #1 (A3921078) and OPT Pivotal #2 (A3921079): OPT Pivotal #1 and OPT Pivotal #2 are 52-week, randomized, double-blind, placebo-controlled, parallel-group studies evaluating the safety and efficacy of tofacitinib 5 mg and 10 mg twice daily in patients who are candidates for systemic therapy or phototherapy. There were over 900 patients randomized into the each of the studies. As previously announced in April 2014, the OPT Pivotal #1 and OPT Pivotal #2 studies showed that tofacitinib, as a 5 mg or a 10 mg dose taken as a pill twice daily, met the primary efficacy endpoints of statistically significant superiority over placebo at Week 16 in the proportion of subjects achieving a PGA response of “clear” or “almost clear” skin, and the proportion of subjects achieving at least a 75% reduction in Psoriasis Area and Severity Index (PASI75).
OPT Compare (A3921080): A 12-week, Phase 3 study comparing the efficacy and safety of tofacitinib 5 mg and 10 mg twice daily to high-dose ENBREL® (etanercept) 50 mg twice weekly as well as to placebo. There were 1,106 patients enrolled in this study.
OPT Extend (A3921061): A long-term extension study evaluating the safety and tolerability of tofacitinib. Patients who participated in the Phase 2 trial or any of the other Phase 3 studies had the option, if eligible, to enroll in this study.
About Plaque Psoriasis
Psoriasis is a chronic, immune-mediated disease, affecting primarily the skin but also other organs, such as nails and joints. It affects approximately two-to-three percent of people worldwide and 7.4 million people in the United States.1,2,3,4,5,6,7 Due to inconsistent response to treatment, adverse effects, and the limited persistence of therapeutic effects of some therapies, a need for additional therapies for patients with moderate-to-severe chronic plaque psoriasis remains.8,9,10 According to recent published surveys, approximately 50 percent of patients with psoriasis are dissatisfied with their treatment and under-treatment represents a significant problem. Even though guidelines typically state that moderate-to-severe patients are candidates for systemic therapy – e.g., medicines given by mouth or an injection - many adult plaque psoriasis patients appear to be undertreated. Approximately 30 percent of treated moderate patients and 22 percent of treated severe patients receive only topical therapies like ointments and creams in the U.S.11
XELJANZ® (tofacitinib citrate) 5 mg Tablets RA U.S. Label Information
Tofacitinib is currently approved in more than 20 countries around the world for the treatment of moderate-to-severe rheumatoid arthritis. In the U.S., the brand name for tofacitinib is XELJANZ® (ZEL’ JANS’), and it is approved at the 5 mg dose for the treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate.
XELJANZ is a prescription medicine called a Janus kinase (JAK) inhibitor. XELJANZ is used to treat adults with moderately to severely active rheumatoid arthritis in which methotrexate did not work well.
It is not known if XELJANZ is safe and effective in people with Hepatitis B or C.
XELJANZ is not for people with severe liver problems.
It is not known if XELJANZ is safe and effective in children.
